I have read articles and forum debates for more than a year now, and of course a lot of questions become important, some of them long time after the choice had to be taken. For example:
In Denmark and maybe in other northwest European countries, it seems to be that VCD (Velcade, dexamethasone and cyclophosphamide) is preferred for induction before autologous stem cell transplantation (ASCT).
What is the standard in the US and in other countries, or at specific treatment centres, and why?
Does anyone here know about the rationale behind choosing one or another combination?
Best regards,
lev
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Lev - Name: Lev
- Who do you know with myeloma?: Me
- When were you/they diagnosed?: June 2014
- Age at diagnosis: 57
Re: Induction before ASCT - which combination & why?
In the forum sidebar is a set of links to poll results asking what initial (induction) therapy myeloma patients got in various countries around the world. Since many (most?) forum participants are younger, and since stem cell transplantation is very frequently part of initial therapy for younger patients, especially outside the U.S., the poll results should help answer your question as to what treatments are common pre-transplant.
I think you would see a lot more use of RVD (Revlimid, Velcade, and dex) in countries outside the U.S. if (a) there were trial results supporting an official approval of the treatment regimen as initial therapy, and (b) it didn't cost so much. The lack of an official approval for upfront Rd (Revlimid and dex) use is a significant reason you rarely saw the regimen used as initial therapy outside the U.S. Ditto for Revlimid as maintenance therapy.
It also is easy to justify the use of VCD as initial therapy because VCD is a comparatively inexpensive treatment regimen, has shown good results in several studies, and is similar to a regimen such as Velcade, melphalan, and prednisone (VMP), which is officially approved as initial therapy in most countries.
The reason I think you would see more use of RVD outside the U.S, all things being equal, is because RVD probably yields deeper responses than VCD, and, rightly or wrongly, there is a growing belief among myeloma specialists that targeting the deepest possible response during treatment is a good thing. This belief isn't universally held, however, which is one of the reasons (but not the only reason) I think you see VCD recommended by the Mayo Clinic for most newly diagnosed, transplant-eligible myeloma patients.
I think you would see a lot more use of RVD (Revlimid, Velcade, and dex) in countries outside the U.S. if (a) there were trial results supporting an official approval of the treatment regimen as initial therapy, and (b) it didn't cost so much. The lack of an official approval for upfront Rd (Revlimid and dex) use is a significant reason you rarely saw the regimen used as initial therapy outside the U.S. Ditto for Revlimid as maintenance therapy.
It also is easy to justify the use of VCD as initial therapy because VCD is a comparatively inexpensive treatment regimen, has shown good results in several studies, and is similar to a regimen such as Velcade, melphalan, and prednisone (VMP), which is officially approved as initial therapy in most countries.
The reason I think you would see more use of RVD outside the U.S, all things being equal, is because RVD probably yields deeper responses than VCD, and, rightly or wrongly, there is a growing belief among myeloma specialists that targeting the deepest possible response during treatment is a good thing. This belief isn't universally held, however, which is one of the reasons (but not the only reason) I think you see VCD recommended by the Mayo Clinic for most newly diagnosed, transplant-eligible myeloma patients.
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JimNY
Re: Induction before ASCT - which combination & why?
Hi JimNY,
Thanks for your answer. And the reference to the sidebar ... It is good to have the statistics, but I am very interested in the scientific rationale behind choosing VCD or the other combinations.
Best regards,
lev
Thanks for your answer. And the reference to the sidebar ... It is good to have the statistics, but I am very interested in the scientific rationale behind choosing VCD or the other combinations.
Best regards,
lev
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Lev - Name: Lev
- Who do you know with myeloma?: Me
- When were you/they diagnosed?: June 2014
- Age at diagnosis: 57
Re: Induction before ASCT - which combination & why?
Hi Lev,
I understood your questions to be those that you outlined in these sentences:
I pointed to where you can find data shedding light on the first question – what's standard in the different countries – and gave you my sense of what the reason is for the differences in treatment regimens across countries and also across myeloma specialists and centers in the U.S. Those reasons include both different interpretations of scientific evidence and, probably more importantly, cost and legal considerations.
So I guess I'm missing why you feel your questions haven't been answered.
I will say that, if you believe that scientific reasons are the main explanation for differences in treatment patterns across countries, you are, as we say here in the U.S., "barking up the wrong tree." Rightly or wrongly, financial considerations play a very significant role, particularly in differences between the U.S. and the rest of the world, but also between, say, the UK and the rest of Europe.
Differences in the interpretation of scientific evidence do probably play more of a role, on the other hand, in differences between different U.S. treatment centers and their approaches to treating newly diagnosed patients.
I understood your questions to be those that you outlined in these sentences:
What is the standard in the US and in other countries, or at specific treatment centres, and why?
Does anyone here know about the rationale behind choosing one or another combination?"
I pointed to where you can find data shedding light on the first question – what's standard in the different countries – and gave you my sense of what the reason is for the differences in treatment regimens across countries and also across myeloma specialists and centers in the U.S. Those reasons include both different interpretations of scientific evidence and, probably more importantly, cost and legal considerations.
So I guess I'm missing why you feel your questions haven't been answered.
I will say that, if you believe that scientific reasons are the main explanation for differences in treatment patterns across countries, you are, as we say here in the U.S., "barking up the wrong tree." Rightly or wrongly, financial considerations play a very significant role, particularly in differences between the U.S. and the rest of the world, but also between, say, the UK and the rest of Europe.
Differences in the interpretation of scientific evidence do probably play more of a role, on the other hand, in differences between different U.S. treatment centers and their approaches to treating newly diagnosed patients.
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JimNY
Re: Induction before ASCT - which combination & why?
Yes, since different approaches are chosen in different countries/different hospitals, my question is still
"Does anyone here know about the rationale behind choosing one or another combination?"
"Does anyone here know about the rationale behind choosing one or another combination?"
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Lev - Name: Lev
- Who do you know with myeloma?: Me
- When were you/they diagnosed?: June 2014
- Age at diagnosis: 57
Re: Induction before ASCT - which combination & why?
Hi Lev,
JimNY can correct me if I am wrong, but I think he is assuming that most patients realize that there are 3 main classes of therapies for transplant eligible patients that are considered the most effective therapies - proteasome inhibitors (bortezomib, carfilzomib), IMIDs (thalidomide, lenalidomide, pomalidomide) and autos (high dose melphalan). You need stem cells to use high dose melphalan (auto) so at least one of the other two classes is typically used for induction. I think one thing every patient/doctor agrees on is that at least one novel agent should be used during induction.
The studies seem clear that for optimal initial response the combination of a PI/IMID/steroid or a PI/alkylator/steroid should be used. They have done 4 drug combo studies but most doctors recommend a 3 drug combo for optimal response. Not every patient is interested in optimal initial response. For example, if a patient has to travel 2 hours to get to an infusion center they may prefer an oral combo (REV/DEX) to avoid all of that travel.
I will discuss how my doctor came up with my induction as an example. I have mentioned before that my induction was Velcade/Doxil/DEX. Even knowing that the others are more likely to get a better initial response I would still use the same induction if I was newly diagnosed today. The reason is that IMO it is important to hit the myeloma with as many different classes of therapies as possible early in disease course. Cytoxan and melphalan are both alkylators while Doxil is in a different class of drugs (anthracycline). I was planning on doing a full allo with high dose melphalan after getting to CR so I knew I would be getting the benefit of the alkylators as part of my early therapy when I did the allo.
There is another reason I went with PI based induction that newly diagnosed patients may want to consider. My doctor wanted to avoid using IMIDs prior to my allo since IMIDs are synergistic with the immunotherapy of the donor immune system. If I ever needed to treat after my allo she thought it would be beneficial to be able to introduce the IMIDs with the additional immunotherapy I would be using (DLI's which are additional infusions of donor cells) to a patient with no prior IMID exposure. With elotuzumab and daratumamab being close to being approved and knowing they pair well with IMIDs, IMO it would be beneficial to introduce those drugs to an IMID naïve patient. Note the ELOQUENT trials that are likely to lead to ELO approval recruited patients that had limited prior IMID exposure. DARA does have single agent activity but it will likely be more effective when paired with an IMID.
I hope that helps answer your question. Myeloma therapy is as much art as science currently and it should depend on the goals/situation of the individual patient as to what the induction therapy that is used in my opinion. One size does not fit all.
Mark
JimNY can correct me if I am wrong, but I think he is assuming that most patients realize that there are 3 main classes of therapies for transplant eligible patients that are considered the most effective therapies - proteasome inhibitors (bortezomib, carfilzomib), IMIDs (thalidomide, lenalidomide, pomalidomide) and autos (high dose melphalan). You need stem cells to use high dose melphalan (auto) so at least one of the other two classes is typically used for induction. I think one thing every patient/doctor agrees on is that at least one novel agent should be used during induction.
The studies seem clear that for optimal initial response the combination of a PI/IMID/steroid or a PI/alkylator/steroid should be used. They have done 4 drug combo studies but most doctors recommend a 3 drug combo for optimal response. Not every patient is interested in optimal initial response. For example, if a patient has to travel 2 hours to get to an infusion center they may prefer an oral combo (REV/DEX) to avoid all of that travel.
I will discuss how my doctor came up with my induction as an example. I have mentioned before that my induction was Velcade/Doxil/DEX. Even knowing that the others are more likely to get a better initial response I would still use the same induction if I was newly diagnosed today. The reason is that IMO it is important to hit the myeloma with as many different classes of therapies as possible early in disease course. Cytoxan and melphalan are both alkylators while Doxil is in a different class of drugs (anthracycline). I was planning on doing a full allo with high dose melphalan after getting to CR so I knew I would be getting the benefit of the alkylators as part of my early therapy when I did the allo.
There is another reason I went with PI based induction that newly diagnosed patients may want to consider. My doctor wanted to avoid using IMIDs prior to my allo since IMIDs are synergistic with the immunotherapy of the donor immune system. If I ever needed to treat after my allo she thought it would be beneficial to be able to introduce the IMIDs with the additional immunotherapy I would be using (DLI's which are additional infusions of donor cells) to a patient with no prior IMID exposure. With elotuzumab and daratumamab being close to being approved and knowing they pair well with IMIDs, IMO it would be beneficial to introduce those drugs to an IMID naïve patient. Note the ELOQUENT trials that are likely to lead to ELO approval recruited patients that had limited prior IMID exposure. DARA does have single agent activity but it will likely be more effective when paired with an IMID.
I hope that helps answer your question. Myeloma therapy is as much art as science currently and it should depend on the goals/situation of the individual patient as to what the induction therapy that is used in my opinion. One size does not fit all.
Mark
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Mark11
Re: Induction before ASCT - which combination & why?
Mark11,
You are clearly very knowledgable about multiple myeloma treatments.
May I ask why you say that "it is important to hit the myeloma with as many different classes of therapies as possible early in the disease course"?
I have also read that, during induction, one should not use more than a few novel agents, lest the myeloma develop resistance to them.
You are certainly right about myeloma therapy being as much art as science, given the current state of knowledge.
From a patient's point of view, it sometimes seems as if there is no clear way to make decisions about treatment. Even the discussed target goal of obtaining as much of a complete response (CR) as possible during induction is controversial, if one is looking at maximizing survival time. There are patients who obtain a CR, but relapse early and then progress, and those who never obtain a CR, but are able to hold at a given plateau of cancer load for long periods of time. Or at least that is my understanding.
You are clearly very knowledgable about multiple myeloma treatments.
May I ask why you say that "it is important to hit the myeloma with as many different classes of therapies as possible early in the disease course"?
I have also read that, during induction, one should not use more than a few novel agents, lest the myeloma develop resistance to them.
You are certainly right about myeloma therapy being as much art as science, given the current state of knowledge.
From a patient's point of view, it sometimes seems as if there is no clear way to make decisions about treatment. Even the discussed target goal of obtaining as much of a complete response (CR) as possible during induction is controversial, if one is looking at maximizing survival time. There are patients who obtain a CR, but relapse early and then progress, and those who never obtain a CR, but are able to hold at a given plateau of cancer load for long periods of time. Or at least that is my understanding.
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MrPotatohead - Name: MrPotatohead
- Who do you know with myeloma?: Me
- When were you/they diagnosed?: March, 2015
- Age at diagnosis: 65
Re: Induction before ASCT - which combination & why?
Hi Mr. Potatohead,
Thanks for the compliment. Hopefully the carfilzomib is continuing to work to get your myeloma under control.
Do not forget that when I write I am mostly writing for younger patients. I try to remember to put something like for younger patients or transplant eligible patients before I write something to make sure everyone understands that. The "average" myeloma patient is 70 years old and only 25% or so of myeloma patients in the US do autos so it appears that many (most) patients are not transplant eligible. I also write for the benefit of high risk patients. Most everything you read is negative regarding outcomes for high risk patients so I try and give an example of a high risk patient having a good outcome.
To your question, here is an excellent article that Dr. Gareth Morgan wrote for the Beacon.
"The evolutionary nature of multiple myeloma is important because the related subclonal cells, each derived from a myeloma stem cell that is subtly different, compete for space to grow within the bone marrow.
In this context, treatment can be considered as a “selective pressure.” It can kill most subclonal cells, but rare, resistant subclones can survive. And, in this setting, the resistant subclones will have more space to grow, leading to relapse.
Patients and doctors need to take these aspects of the ICH phenomenon into account when considering how to treat myeloma. The diversity that is present means that there are cellular subpopulations that are resistant to single treatments and can be responsible for relapse.
In this respect, using a combination of treatments that kills the maximum number of subclones is an important strategy. Indeed, such a strategy is relevant even if there is a single dominant clone that is not aggressive. That clone, by filling all of the space in the bone marrow, is likely to be suppressing the growth of more aggressive subclones. Using a small number of treatments targeted at just the dominant, less aggressive clone will leave the more aggressive subclones untreated and with more space to grow, leading to relapse."
https://myelomabeacon.org/news/2014/11/03/evolution-intra-clonal-heterogeneity-multiple-myeloma/
For the potential optimal outcome, which I define as a long term drug free remission (functional cure), IMO it is clear that a strategy that uses multiple different lines of therapy is optimal for a transplant eligible patient. For example, I used 7 different classes of therapy in my 8 months of treatment. I get ongoing protection from the donor immune system as well.
"From a patient's point of view, it sometimes seems as if there is no clear way to make decisions about treatment. Even the discussed target goal of obtaining as much of a complete response (CR) as possible during induction is controversial, if one is looking at maximizing survival time. There are patients who obtain a CR, but relapse early and then progress, and those who never obtain a CR, but are able to hold at a given plateau of cancer load for long periods of time. Or at least that is my understanding."
That is my understanding with regard to standard risk patients. Dr. Rajkumar from Mayo wrote an excellent article about that for us here at the Beacon as well. Note that this was first shown with patients that used aggressive, alkylator based therapy. There may be studies that show this with novel agent based sequential therapy. If there are studies that show this with sequential type of therapy, hopefully someone can provide the link. I want to make clear, I am not saying these do not exist, I just never saw it and would be interested in reading it.
"A classic study by Dr. Bart Barlogie’s group looked at the impact of complete response in patients according to their chromosomal abnormalities in their myeloma cells. His group found that most (more than 85 percent) of patients with myeloma lived the same length of time whether they achieved a complete response or not. Only in very high-risk patients, as defined by gene expression profiling, could one see the possible importance of complete response."
https://myelomabeacon.org/news/2013/08/10/complete-response-multiple-myeloma-treatment/
I hope that helps answer your questions.
Mark
Thanks for the compliment. Hopefully the carfilzomib is continuing to work to get your myeloma under control.
Do not forget that when I write I am mostly writing for younger patients. I try to remember to put something like for younger patients or transplant eligible patients before I write something to make sure everyone understands that. The "average" myeloma patient is 70 years old and only 25% or so of myeloma patients in the US do autos so it appears that many (most) patients are not transplant eligible. I also write for the benefit of high risk patients. Most everything you read is negative regarding outcomes for high risk patients so I try and give an example of a high risk patient having a good outcome.
To your question, here is an excellent article that Dr. Gareth Morgan wrote for the Beacon.
"The evolutionary nature of multiple myeloma is important because the related subclonal cells, each derived from a myeloma stem cell that is subtly different, compete for space to grow within the bone marrow.
In this context, treatment can be considered as a “selective pressure.” It can kill most subclonal cells, but rare, resistant subclones can survive. And, in this setting, the resistant subclones will have more space to grow, leading to relapse.
Patients and doctors need to take these aspects of the ICH phenomenon into account when considering how to treat myeloma. The diversity that is present means that there are cellular subpopulations that are resistant to single treatments and can be responsible for relapse.
In this respect, using a combination of treatments that kills the maximum number of subclones is an important strategy. Indeed, such a strategy is relevant even if there is a single dominant clone that is not aggressive. That clone, by filling all of the space in the bone marrow, is likely to be suppressing the growth of more aggressive subclones. Using a small number of treatments targeted at just the dominant, less aggressive clone will leave the more aggressive subclones untreated and with more space to grow, leading to relapse."
https://myelomabeacon.org/news/2014/11/03/evolution-intra-clonal-heterogeneity-multiple-myeloma/
For the potential optimal outcome, which I define as a long term drug free remission (functional cure), IMO it is clear that a strategy that uses multiple different lines of therapy is optimal for a transplant eligible patient. For example, I used 7 different classes of therapy in my 8 months of treatment. I get ongoing protection from the donor immune system as well.
"From a patient's point of view, it sometimes seems as if there is no clear way to make decisions about treatment. Even the discussed target goal of obtaining as much of a complete response (CR) as possible during induction is controversial, if one is looking at maximizing survival time. There are patients who obtain a CR, but relapse early and then progress, and those who never obtain a CR, but are able to hold at a given plateau of cancer load for long periods of time. Or at least that is my understanding."
That is my understanding with regard to standard risk patients. Dr. Rajkumar from Mayo wrote an excellent article about that for us here at the Beacon as well. Note that this was first shown with patients that used aggressive, alkylator based therapy. There may be studies that show this with novel agent based sequential therapy. If there are studies that show this with sequential type of therapy, hopefully someone can provide the link. I want to make clear, I am not saying these do not exist, I just never saw it and would be interested in reading it.
"A classic study by Dr. Bart Barlogie’s group looked at the impact of complete response in patients according to their chromosomal abnormalities in their myeloma cells. His group found that most (more than 85 percent) of patients with myeloma lived the same length of time whether they achieved a complete response or not. Only in very high-risk patients, as defined by gene expression profiling, could one see the possible importance of complete response."
https://myelomabeacon.org/news/2013/08/10/complete-response-multiple-myeloma-treatment/
I hope that helps answer your questions.
Mark
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Mark11
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